The invention relates to new glucocorticoid receptor antagonists for producing a new drug for the prophylaxis and therapy of glucocorticoid-mediated hypogonadism, sexual dysfunctions and/or infertility.
For purposes of the present invention, by “glucocorticoid receptor antagonists” are meant pharmaceuticals capable of competitively inhibiting the action of glucocorticoids by better and more selective binding to the glucocorticoid receptors.
It is known that with advancing age and physical and/or mental stress and in the human body the corticoid level is elevated relative to the level of sex hormones and that exogenous factors such as drug abuse and alcohol abuse can lead to sexual dysfunctions and hypogonadism. These disorders occur as a result of reduced endogenous androgen production, particularly as a result of reduced production of testosterone in the testes and by a “corticoid-mediated” increase in testosterone degradation. Moreover, as a result of hypophyseal suppression, the secretion of ACTH is reduced and, secondary to that, the production of adrenal androgen is also reduced (Hatz, H. J., “Glucocorticoide” [Glucocorticoids], page 231, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998 [publisher]).
Various attempts have been made to treat the foregoing disorders. The drugs used for this purpose are only partly suitable in terms of their efficacy, selectivity and adverse reactions to which they give rise.
For example, EP 0057117 discloses as a glucocorticoid receptor antagonist the compound 11β-(4-dimethylamino)phenyl-17β-hydroxy-17α-propyn-1-yl-estra-4,9-dien-3-one, RU 38486, which binds to the progesterone receptor and glucocorticoid receptor almost equally strongly and is currently permitted for therapeutic termination of pregnancy in its early stages [Moguilewsky, M., Philibert, D., in: The Antiprogestin Steroid 11β-(4-dimethylamino)phenyl-17β-hydroxy-17α-propyn-1-yl-estra-4,9-dien-3-one (RU 38486) and Human Fertility Control, page 87, Plenum Press, New York, London, 1985, (editors: Baulieu, E. E. and Segal, S. J.)] or for the treatment of Cushing's syndrome [Nieman, L. K., Chrousos, G. P., Kellner, C. K., Spitz, I. M., Nisula, B. C., et al., J. Clin. Endocr. Metab. 61, 536 (1985)]. The use of antiglucocorticoids for the treatment of anxiety disorders is described in the application WO 95/04536 (Peeters, B.).
Gebhard, R., describes in the patents EP 0 683 172 A1 and EP 0 793 541 A1 and in Bioorganic & Medicinal Chemistry Letters 7, 2229-2234 (1997) a number of 11,21-bisphenyl-19-norpregnanes for the treatment of diseases mediated by certain glucocorticoids, such as Cushing's syndrome, diabetes, glaucoma, depression, arteriosclerosis, adiposity, high blood pressure, sleep disorders and osteoporosis.
Until now, with the exception of 11β-(4-dimethylamino)phenyl-17β-hydroxy-17α-propyn-1-yl-estra-4,9-ien-3-one (RU 38 486), a very strongly but not very selectively binding substance, no compound has been developed as an antiglucocorticoid for therapy. One compound (ORG 34 517) is currently in phase II/III clinical trials for depression as the indication [PharmaBusiness 51, 152 (2002)].